CD8+CD122+ T Cells, a Newly Identified Regulatory T Subset, Negatively Regulate Graves’ Hyperthyroidism in a Murine Model

Abstract

Graves' disease is a thyroid-specific autoimmune disease mediated by stimulatory autoantibodies against the TSH receptor (TSHR). We have previously shown in our mouse model with adenovirus expressing the TSHR that antibody mediated depletion of CD4(+)CD25(+) regulatory T cells (Tregs) enhances incidence and severity of hyperthyroidism in resistant and susceptible mouse strains, respectively. These data indicate that balance between effector T cells and Tregs is critical for disease development. This study was designed to evaluate the role played by another recently identified type of Treg, CD8(+)CD122(+) T cells, in our mouse model to delineate the significance of different types of Tregs in Graves' disease. Flow cytometry analysis showed that CD4(+)CD25(+) and CD8(+)CD122(+) T cells are distinct cell types, and anti-CD122 antibody effectively and selectively depleted CD8(+)CD122(+) T cells. As for CD4(+)CD25(+) Treg, CD8(+)CD122(+) T cell depletion increased the incidence of hyperthyroidism both in resistant and susceptible mice. Of interest, intrathyroidal lymphocytic infiltration was observed in some CD8(+)CD122(+) T cell-depleted, hyperthyroid resistant mice. These results indicate that in addition to CD4(+)CD25(+) T cells, CD8(+)CD122(+) T cells also play a crucial role in disease susceptibility in mouse Graves' disease. Thus, different types of Tregs appear to be involved in tolerance to a self-antigen, the TSHR.

B Cells, Dendritic Cells, and Macrophages Are Required To Induce an Autoreactive CD4 Helper T Cell Response in Experimental Epidermolysis Bullosa Acquisita

“…The results from Ag-specific T cell detection in vitro and CD4 T cell depletion in vivo suggested that vWFA2 fused to intein induced vWFA2-specific CD4 T cells, which supported autoantibody production in this model. In some autoimmune diseases, CD8 T cells were shown to modulate autoantibody production (44)(45)(46). However, in both pemphigoid and pemphigus, CD8 T cells were not required for autoantibody production after cell transfer into immunodeficient mice (14,15).…”

Iodine-131 therapy alters the immune/inflammatory responses in the thyroids of patients with Graves' disease

“…The development of GD is influenced by various genetic and environmental factors and the interactions between them (1). GD pathogenesis is generally characterized by abnormalities in T-cell subsets (2,3), innate immune cells (4), and various cytokines, which ultimately decreases immune tolerance and excessively activates B cells, promoting the production of thyroid stimulating hormone (TSH) receptor antibody (TRAb). The biased activation of helper T (Th) cells has an important role in GD development (5,6) and the imbalance of Th1/Th2 cell immunity may result in a shift toward the Th2-type immune response (7).…”

A naturally occurring CD8+CD122+ T-cell subset as a memory-like Treg family

“…17 Moreover, CD8 1 CD122 1 Tregs could suppress other autoimmune diseases in animal models. Saitoh et al 42 found that depletion of CD8 1 CD122 1 T cells increased the incidence of autoimmune Graves' hyperthyroidism in a murine model, suggesting that they play an essential role in suppressing autoimmune hyperthyroidism. CD8 1 CD122 1 and CD4 1 CD25 1 Tregs cooperatively prevented CD4 1 T cell-mediated colitis.…”